Understanding the earliest pathological changes in Alzheimer disease (AD) is critical for improving early intervention strategies. However, the relationship between amyloid plaque characteristics and early behavioral and molecular alterations remains unclear. We used 6-month-old female APPswe/PS1dE9 mice, a model of early amyloid-dominant pathology, to assess cognition and emotionality across a battery of behavioral tests. Amyloid plaques were quantified using Congo red staining; RT-qPCR and GFAP immunoreactivity were used to assess molecular and glial changes. APPswe/PS1dE9 mice exhibited increased anxiety-like behavior without significant changes in overall locomotor activity. Small plaques (<100 μm2) predominated across all regions; however, behavioral measures of hyperactivity and anxiety correlated specifically with the density and size of large (>200 μm2) plaques. Gene expression changes, including altered SYP, IGF1, TNF, and IL6 expression, were observed primarily in the midbrain and did not correlate with amyloid plaque characteristics. These findings demonstrate that large amyloid plaques, rather than total plaque burden, are selectively associated with early behavioral alterations in APPswe/PS1dE9 mice. Moreover, the midbrain emerges as an early site of molecular dysregulation despite limited plaque deposition. Together, these results support the use of 6-month-old APPswe/PS1dE9 mice as a model of early, amyloid-dominant stages of AD.